In this issue
In this issue: Eur. J. Immunol. 6'12
The cover image is based on hematoxylin and eosin staining of a section of colon from a GITRL transgenic mouse; the original non-manipulated image can be seen in the article by Carrier et al. (pp 1393–1404). In this article, the authors show that the constitutive expression of GITRL on APCs (MHC class II+ cells) leads to increased T-cell activation and lymphocytic infiltration into multiple organs, including the lung, liver, intestinal tract, pancreas, salivary gland, and kidney; however, despite such infiltration, autoimmune disease (e.g. inflammatory bowel disease) was not detected. The observed increase in Foxp3-IL-10-producing Tr-1-like cell numbers (potentially driven by the increased IL-27 production) is proposed by the authors to explain this.
Location, location, location: What matters for FOXP3
The forkhead transcription factor FOXP3 is an important determinant of regulatory T (Treg) cells. Treg cells have great therapeutic potential for controlling autoimmunity and for the induction of transplantation tolerance. Although the expression of FOXP3 is essential for Treg-cell development, FOXP3 may have additional functions in conventional T cells, where it is transiently expressed after activation without conferring a regulatory phenotype. In this issue, Magg et al. describe for the first time that FOXP3 is constitutively located in the nucleus in Treg cells while it mainly localises in the cytoplasm in activated conventional T cells. They describe two novel nuclear export sequences responsible for nucleo-cytoplasmic shuttling of FOXP3 and, furthermore, find that induction of suppressor function in conventional T cells strictly depends on its subcellular localisation. Over-expression of a FOXP3-mutant with both export sequences disrupted induces regulatory capacity in conventional T cells. These findings are highly relevant for the development of efficient Treg-based immunotherapeutic strategies.
Anti-IL-17 treatment attenuates granulomatous inflammation
IL-17 is a signature cytokine of Th17 cells implicated in the induction and progression of chronic inflammatory diseases. Several studies in C57 BL/6 mice, immunized with SEA in CFA, and subsequently infected with S. mansoni have shown that severe hepatic granulomatous inflammation is correlated with high levels of IL-17. In this issue, using the S. japonicum larvae infection model in C57 BL/6 mice, Zhang et al. report that the dynamic expression of IL-17 and cytokines/chemokines involved in the induction and effector function of Th17 cells occurs in parallel with hepatic granulomatous inflammation. Treatment of S. japonicum-infected mice with an IL-17-neutralizing mAb resulted in a significant down-modulation of granulomatous inflammation and hepatocyte necrosis. This protection was associated with a lower expression of proinflammatory cytokines/chemokines, such as IL-6, IL-1β, CXCL1, and CXCL2, and a reduced number of infiltrating neutrophils. These observations indicate a pathogenic role of Th17/IL-17 in the hepatic immunopathology of S. japonicum-infected mice.
Do adoptively transferred Treg cells go home?
CD4+Foxp3+ regulatory T (Treg) cells are specialized lymphocytes which prevent autoimmunity in normal hosts and are compartmentalized anatomically within secondary lymphoid organs. In this issue, Lieberman et al. answer the question: do adoptively transferred Treg cells return to their site-of-origin? Indeed, Treg cells do go home, though not exclusively and not directly. The authors report that Treg cells isolated from cervical lymph nodes accumulate within cervical lymph nodes of recipient mice over weeks following adoptive transfer. Interestingly, recently activated Treg cells (as indicated by surface CD69 expression) accumulate within cervical lymph nodes more efficiently than their CD69-negative counterparts, suggesting this site-specific localization may be mediated by locally expressed antigens recognized by Treg-cell T-cell receptors (TCRs). These data suggest that within any given lymph node two populations of Treg cells exist: CD69-positive “home” Treg cells recognizing local antigen, and CD69-negative “away” Treg cells which are just passing through.
SIN-fully regulated: mTORC2 signaling regulates Treg-cell development
Mammalian target of rapamycin (mTOR) signaling regulates T-cell immunity and tolerance. The mTOR functions via two independent protein complexes called mTOR complex (mTORC)1 and mTORC2, yet the mechanisms through which the mTORCs regulate T-cell development and immunity remain poorly understood. In this issue, Chang et al. explore how the genetic disruption of Sin1, a critical adaptor protein required for mTORC2 integrity and function, affects T-cell development and function. Although Sin1 deficiency impairs mTORC2-dependent T450 and S473 phosphorylation of Akt — a critical mediator of pro-survival and pro-growth signals in developing and mature T cells — the authors found that Sin1 deficiency does not compromise thymic T-cell development or survival. Nor does Sin1 deficiency affect peripheral T-cell growth and proliferation. Rather, the loss of Sin1 enhanced thymic nTreg-cell development. These data reveal that the pro-growth and survival functions of Akt are regulated via the PI3K-mediated PDK1 activation and are independent of mTORC2-mediated Akt phosphorylation in T cells.
Subcutaneous insulin for preventing autoimmune diabetes: Lost in (clinical) translation?
Clinical trials aimed at preventing Type 1 diabetes have so far been disappointing. In the case of subcutaneous insulin treatment, Brezar et al. suggest that one pitfall lies in the translation of preclinical mouse studies into human trials. When two key aspects of these trials (i.e. lower insulin regimens and a shorter treatment period) were translated back into NOD mice, only a delayed onset but no significant diabetes protection was achieved, even at high insulin doses. Mechanistic studies suggest that the effect is mainly one of transient β-cell “rest”, with no significant immune modulation of islet-specific CD8+ T-cell responses. These findings have important implications for the design of novel insulin-based prevention trials.